The proposed work is designed to determine the physiologic and pathophysiologic importance of adenosine in the control of heart rate. It will examine the effect of exogenous and endogenous adenosine on the sinoatrial (SA) node, the physiological cardiac pacemaker, both in intact animals with chronic cardiovascular instrumentation and in isolated atria and sinoatrial node preparations. One major focus of the work will be to characterize the adenosine receptor responsible for adenosine's negative chronotropic action. This will be done using pharmacological studies of the negative chronotropic potency order of structural analogues of adenosine, the use of specific adenosine receptor antagonists, receptor binding studies and measurements of cyclic nucleotide levels in SA nodal tissue. Another major focus of the work will be to determine the existence and extent of any anti- adrenergic component of adenosine's inhibitory effect on the SA node. The anti-adrenegic negative inotropic effect of adenosine in the dog, the existence of which in this species is a matter of some controversy, will also be determined. A third major focus of the work will be to evaluate the importance of endogenous adenosine as a controller of heart rate in certain stressful or pathophysiological states using pharmacological modulators of adenosine's action and also measurements of endogenous adenosine levels. In each of the situations to be studied - hypoxia, focal SA node ischemia, heart failure and diabetes - there is elevated adenosine production or an altered sensitivity to adenosine or both. The study will contribute to our basic understanding of heart rate control and to the regulatory importance of adenosine. Moreover, it will contribute to a better understanding of the etiology and possible treatment of certain cardiac arrhythmias found in man.